1. Academic Validation
  2. Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer

Aberrant methylation of WD-repeat protein 41 contributes to tumour progression in triple-negative breast cancer

  • J Cell Mol Med. 2020 Jun;24(12):6869-6882. doi: 10.1111/jcmm.15344.
Han Wang 1 Dan Wu 2 Liangliang Cai 1 Xiaohong Li 3 Zhiming Zhang 4 Shuai Chen 2 1 5 6
Affiliations

Affiliations

  • 1 Translational Medicine Research Center (TMRC), School of Pharmaceutical Science, Xiamen University, Xiamen, Fujian, China.
  • 2 Department of oncology, Xiamen Fifth hospital, Xiamen, China.
  • 3 Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 4 Department of Breast Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 5 Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
  • 6 Xiamen Key Laboratory of Otolaryngology-Head and Neck Surgery, Xiamen, China.
Abstract

WD-repeat proteins are implicated in a variety of biological functions, most recently in oncogenesis. However, the underlying function of WD-repeat protein 41 (WDR41) in tumorigenesis remains elusive. The present study was aimed to explore the role of WDR41 in breast Cancer. Combined with Western blotting and immunohistochemistry, the results showed that WDR41 was expressed at low levels in breast Cancer, especially in triple-negative breast Cancer (TNBC). Using methylation-specific PCR (MSP), we observed that WDR41 presented hypermethylation in MDA-MB-231 cells. Methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) management increased the expression of WDR41 in MDA-MB-231 cells, but not in MCF-10A (normal mammary epithelial cells) or oestrogen receptor-positive MCF-7 breast Cancer cells. WDR41-down-regulation promoted, while WDR41-up-regulation inhibited the tumour characteristics of TNBC cells including cell viability, cell cycle and migration. Further, WDR41-up-regulation dramatically suppressed tumour growth in vivo. Mechanistically, WDR41 protein ablation activated, while WDR41-up-regulation repressed the Akt/GSK-3β pathway and the subsequent nuclear activation of β-catenin in MDA-MB-231 cells, and 5-aza-dC treatment enhanced this effect. After treatment with the Akt Inhibitor MK-2206, WDR41-down-regulation-mediated activation of the GSK-3β/β-catenin signalling was robustly abolished. Collectively, methylated WDR41 in MDA-MB-231 cells promotes tumorigenesis through positively regulating the Akt/GSK-3β/β-catenin pathway, thus providing an important foundation for treating TNBC.

Keywords

AKT/GSK-3β/β-catenin pathway; WDR41; methylation; triple-negative breast cancer.

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